Aliphatic diamines and salts thereof



ALIPHATIC DIAMINES AND SALTS THEREOF Joseph Lester Szabo, Drexel- Hill,and William F. Bruce, Havertown, Pa, assignors to American Home ProductsCorporation, New York, N. Y., a corporation of Delaware No Drawing.Original application August 26, 1952, Se-

rial No. 306,514, now Patent No. 2,739,981, dated March 27, 1956.Divided and this application January 18, 1956,v Serial No. 559,770

2 Claims. c1. 260 -501) This invention relates to derivatives ofethylene diamine and its homologues and, more particularly, to newmonoand poly-substituted-amino-alkylene diamine salts.

Certain substituted alkylenc diamines have been found withbronchodilator and antihistaminic action and also found useful asintermediates in the preparation of desired organic compounds. Inaddition, it. has been discovered that many of these compounds areuseful for separating penicillin from aqueous solutions by forming asalt therewith. Many of the penicillin salts are substantially insolubleor, at most, sparingly soluble in an aqueous medium. One is thus able toisolate and, ifdesired, to purify penicillin since it has been foundthat the latter canbe almost quantitatively removed from its solution bythe addition of two molecules of penicillin to these particulardiamines.

As an additional discovery, these substantially insoluble or sparinglysoluble salts of penicillin have been found to be valuable from apharmacological aspect since they are relatively non-toxic and, when incontact with body fluids, slowly release penicillin for utilization incombatting bacterial infections. A prolonged antibiotic effect can thusbe achieved without difliculty. By the use of these: new penicillinsalts, one greatly reduces'the number of injections required to-sustainthe desired blood level concentration of penicillin.

The useful diamines are those falling within the following generalformulae: RNH(CH ),,NH

where R, R and R may represent either aliphatic, aromatic, alicyclic orheterocyclic radicals with and without substituents on the rings. In thealkylene portion of the molecule, n is intended, to represent a numeralgreater than 1, preferably from 2 to 12'.

v The substituents, which may be of the aryl, alicyclic and heterocyclicrings as well as ,onthe alkyl chain, may comprise one or more alkyl,alkoxy, halogen, nitro, amino, 0x0 or hydroxy ring substituents. As amatter of fact, with the exception of strong acid or oxidizing groups,no substituent has been found which interferes with the reaction of theN,N'-di-substituted secondary wherein R, R and n are the same asindicated before, is isolated and is then hydrogenated by catalyticreduction or by a metal-alcohol or metal-acid combination.

Where, for example, the radical R, R or R itself contains a double bond,the hydrogenation orreductionmay United States Patent-O "ice R- NH (CH)-,,NH or RR N'( CH ),,NH

may involve the reduction of an amide such as Y RCONH( CH NH,

using metal hydrides for example, or an amination of a halogen compoundsuch as RR N (,CH ),,Cl utilizing ammoniacal ethanol.

The poly-substituted bases can alternatively be made by the reaction ofanalkyl'ene d'ihalide, such as the dibrornide, dichloride or diiodide,with the appropriate amine.

Substituted alkylene diamine salts may also be prepared by interactingapproximately equivalent quantities of a salt. of the alkylenediamine,such asthe dihydrochloride, dihyd'robromide, dinitrate, diformate,diacetate or other suitable salt of ethylene diamine and an acid,wi'th'formaldehyde either in the form of its aqueous solution or as thesolid polymeric form, paraformaldehyde, and with a compound containingan active hydro gen such as the alpha-hydrogen of thiophenes, picolines,quinaldines, phenols, aliphatic nitro-compounds, organic acids andesters, and open-chain and cyclic aldehydes and ketones in a suitablesolvent such as water, alcohol or other organic solvents or mixturesthereof, resulting in an N,N-disubstitutedalkylene diamine salt whichmay be transposed intothe free base by alkali treatment.

'It the product obtained is to be used for the preparation of penicillincompounds, it is best used as a salt rather than in the form of thefree'base to avoid inactivating the penicillin. The. salts may be formedfrom the free base by dissolving the latter in a solvent, such as ether,towhich is added the proper acid, depending on the particular salt.desired.

The salts formed may be either mono-salts ordi-salts depending on theamounts of base and acid used. Thus, if one mol. equivalent each of acidand base'were used,

the mono-salt would. be formed. On the other hand, if two mol.equivalents, or an excess. of acid, areused'with one mol. of thediamine, the di-salt would be formed. For making penicillin salts fromthe diamines, one would generally desire. the double salt instead of themono-salt since two mols. of penicillin would be combined when using theformer, whereas only one mol. of penicillin combines with the mono-salt.

Inorganic or organic acids may be used in forming the salts from thefree. base, amino-substituted alkylene diamines. The most commoninorganic acids are hydrochloric, sulfuric, phosphoric, nitric orhydrobromic acids, these forming in general sparingly water-solublesalts. On the other hand organic aliphatic, carboxylic acids areparticularly preferred because in general they have been ,1 to 6 carbonatoms as formic, acetic, propionic, butyric,

Preparation N0. 1 of condensing benzaldehyde with ethylene diamine.

isovaleric, glycolic, lactic, gluconic, amino acetic, and crotonic acidsas examples of the mono-carboxylic type. Examples of the di-carboxylicclass found to be particularly useful are theacids of 3 to 6 carbonatoms 'as malonic, succinic, gluta'ric, adipic, malic, tartaric,

glutamic, maleic and fumaric acids. In the class of the tri-carboxylicacids, citric, iso-citric, and aconitic acids have been foundparticularly useful. While others will form suitable salts, theseorganic compounds mentioned will form highly desirable soluble saltswhose solubility in water is at least about by weight per unit of liquidvolume at about 30 C.

By the term water-soluble salt, the applicants follow the generallyunderstood meaning. In order to avoid any question as to meaning, theapplicants prefer to consider a water-soluble salt to be one which willdissolve in water to the extent of at least about 5% by weight per unitof liquid volume at 30 C. A sparingly water-soluble salt would be onewhose solubility in water would range from just below this figure toabout 1% by'weight, while a substantially insoluble salt would be onehaving a solubility less than about 1% by weight per unit of liquidvolume. In preparing sparingly water-soluble or substantiallywater-insoluble penicillin salts of the amino-substituted alkylenediamine salts, it is highly advantageous to obtain the penicillin saltsas a precipitated solid from a substantially aqueous medium. Thedesiredsalt may then be easily separated, as by filtration, and purifiedby washing. Thus, the selected alkylene diamine salt is solubilized andreacted with a water-soluble salt of penicillin, The desired penicillinsalt, being either substantially water-insoluble or only sparinglywater-soluble, precipitates from the aqueous medium and is separatedtherefrom.

In the above procedure involving precipitation from an aqueous medium,it has been found advantageous to use relatively soluble diamine saltsin preparing the penicil lin salts thereof since less liquid volume ishandled and therefore losses are likely to be less than if relativelyinsoluble salts were used. While salts made with the inorganic acids canbe used in preparing the penicillin compounds, it has been found thattheir solubility is quite low and well below 5% on a weight basis.Consequently, water-soluble salts and particularly the diacetates,having a solubility in the neighborhood of about or higher have beenfounds especially effective where it is desired to handle relatively lowliquid volumes and therefore high concentrations.

Any of the known soluble penicillin salts may be combined with thepoly-substituted diamines. Thus, one may use the alkali or alkalineearth metal salts of penicillin G, dihydro F, X,'or penicillin K forcombination with the selected diamine. However, the more preferredpenicillin salts are the sodium or potassium salts of penicillin G. Oneor two molecules of any penicillin above indicated will unite with onemolecule of the diamine, depending on the use of the monoor the di-salt.

The following examples are given for specific illustrations but itshould be understood that these are selected for illustration of theinvention and not to be considered limitative.

EXAMPLE 1 N,N'-dibenzylethylenediamine and salts thereofN,N-dibenzylethylenediamine was first prepared by Thedibenzylethylenediamine (23.6 g.) was dissolved in 100 cc. methanolcontaining 0.5 g. Adams platinum catalyst and hydrogenated at 50 lbs.pressure. Slightly more than the theoretical amount of hydrogen wasabsorbed in 45 minutes. 7 The catalyst was filtered olf, washed withmethanol, the filtrate concentrated and the residue frac- 4 tionated.Nearly all of the material distilled 160 and 0.75 mm., n 1.5621.

With Raney nickel catalyst at room temperature little hydrogenabsorption occurred, however, under elevated pressure hydrogenation wentto completion but was much slower than with platinum. The diacetate wasprepared by dissolving 440 g. of the base in about 3 liters of alcoholand slowly adding 220 g. of glacial acetic acid. After standing sometime the crystalline solid was filteredoff and recrystallized from hotalcohol. Long, white needles, M. P. -112.

Calcd.'for C H N -2CH COOH: C, 66.7; H, 7.78; N, 7.78. Found: C, 66.98;H, 7.63; N, 8.38. Solubility 252.9 g. per liter of solution at 30.4 inwater. The dihydrobromide was obtained by adding hydrobromic acid to anaqueous solution of the acetate. Large colorless plates, recrystallizedfrom water, M. P. 300 (ban). Calcd. for C H N -2HBr: N, 6.97; Br, 39.8.Found: N, 6.9; Br, 39.5. Solubility 30.0 g. per liter of solution inwater at 30.4".

The dihydrochloride was obtained from the acetate by addition ofhydrochloric acid and recrystallized from water. Large white plates, M.P. 294 (ban). Calcd. for C H N -2HCl: N, 8.97; c1, 22.4. Found: N, 8.8;Cl. 22.4. Solubility 23.9 g. per liter of solution in water at 30.4.

The dinitrate was obtained by adding nitric acid to a solution of theacetate. Large white plates M. P. 274 (ban). Calcd. for C H N -2HNO N,15.3. Found: N, 14.9. Solubility 9.04 g. per liter of solution at 30.4.

The phosphate was obtained by adding phosphoric acid to a solution ofthe acetate and recrystallized from dilute alcohol. White prisms, M. P.232 (ban). Calcd. for C H N -2H PO N, 6.42; P. 14.2. Found: N, 5.45; P,13.9. Solubility 38.6 g.-per liter of solution at 30.4".

The sulfate was obtained by addition of sulfuric acid to a solution ofthe acetate and recrystallization from alcohol. White plates, M. P.247250. Calcd. for C16H2QN2'H2SO4: C, N, H, S, 9.47. Found: C, 56.37; H,6.43; N, 7.99; S, 9.85. Solubility 15.8 g. per liter of solution at 304.

The thiocyanate was prepared by addition of a solution of sodiumthiocyanate to the acetate and recrystalfrom alcohol, M. P. 211 (ban).

The oxalate, C H N -H C O was obtained as colorless needles fromalcohol, M. P. 2756.

The salts of the lower aliphatic carboxylic acids mentioned hereinabovedid not precipitate out on addition of their aqueous sodium saltsolutions to the solutions of the acetate indicating that these saltswere substantially water-soluble. To obtain these salts from an aqueousmedium, the solutions are evaporated to dryness. A better procedure to'obtain a purified water-soluble product is to solubilize the diaminefree base in an organic solvent such as alcohol, acetone, diethyl ether,etc., and add the free acid also in solution in an organic solvent. Thedesired salt will either precipitate from solution, or the solventsolution may be evaporated to dryness.

' The lactate was prepared by mixing alcoholic solutions of lactic acidand the base, N,N-dibenzyl ethylenediamine. Fine white crystals wereobtained having a melting point of 74 C.

The formate was prepared by adding 4.6 g. of 98-100% formic aciddropwise to 12g. of N,N'-dibenzyl ethylenediamine dissolved in ether. Animmediate precipitate formed. The solid wasbroken up in the ethersuspension and filtered off, washed with ether and dried; M. P. 125-126.The salt may be recrystallized from methylethyl ketone.

The glutarate was prepared as with the formate salt but the additionwas. reversed, using 0.5 g. .of glutaric' 7 acid to which was added 0.91g. of the'free base. M."P.

aseassa cc. of hot alcohol and to it was added a solution of 9.83 gramsof the base, N,N'-dibenzyl ethylenediamine in about cc. alcohol.Crystals gradually formed. After a few days, these were filtered ofi,washed with alcohol and dried in the steam oven. White crystals, M. P.172-174 C. Analysis.-Calculated on the basis of 1 mol. of base combinedwith 1 mol. of acid, N calculated 7.82; found 7.00.

The malate was prepared as above using 5 grams of malic acid and 9 gramsof base in about the same quantities of solvent. White crystals formedand were isolated. An'alysis.-Based on 1 mol. of acid and base, Ncalculated 7.50, found 6.03. Carrying out the same reaction .using 2mols. of acid per m-ol. of base, a salt product was also obtained.Analysis.-N, calcd. 5.5; 2

found, 5.32.

The propionate was prepared in the same manner as above using 5 cc. ofbase and 3.5 cc. of propionic acid with ether as the solvent. Thepropionate was obtained in the form of a sirup.

In obtaining the following group of salts, these were prepared byaddingth'e free base slowly with stirring to a warm solution of the aciddissolved in the indicated solvent. 1

The aconitate was obtained using 1.3 grams of aconitic acid and 1.2grams of base with acetone as'the solvent. M. P. 140-142 dec. r

The tartarate was obtained using 1.5 grams of d tartaric acid and 2.4grams of base, using ethyl alcohol as the solvent. M. P. 215-216.

The-crotonate wasobtained by reacting 1.8 grams of crotonic acid with2.4 grams of base, using ethyl alcohol as the solvent. M. P. -111".

The citrate was obtained using 7.6 grams citric acid and 14.4 gramsbase, ethyl alcohol being the solvent. M. P. 201 c. dec. v The gluconatewas prepared by reacting 7.12 grams of glucono-A-lactone, the solventbeing a mixture of alcohol and water. The salt was obtained in the formof a sirup. v

The glycolate was obtained by reacting 2.48 grams of glycolic acid and4.8 grams of base, with acetone as the solvent, M. P. -121 C.

The glutamate was prepared by reacting 2.5 grams of mono-sodiumglutamate with 2.15 grams of N,N'-dibe'nzyl ethylenediamine diacetate.The sodium salt was dissolved in water, converted to the disodium saltwith 4% NaOH, pH (final) 8.5. This solution was treated with activatedcarbon. To the'colorless filtrate was added a water solution of thediacetate. The glutamate salt had a melting point of 288-289" C.

In the above cases Where solids did not come down immediately, some ofthe solvent was evaporated off, resulting in a precipitationof salt fromthe concentrated solution. In those cases where 'sirups resulted,crystals could sometimes be obtained by evaporation of part of Thebutyrate was obtained by proceeding as above using 5 cc. of base and 4.1cc. of isobutyric acid, with ether as the solvent. The butyrate was alsoobtained in the form of a sirup. t

The valerate was obtained by proceeding as above using 5- cc.- of baseand 4.75 cc. isovaleric acid, with ether as the solvent. A white solidwas formed. Softens about 80, M. P. 82-3. Analysis.N, calculated 8.19;found 8.35.

2 The glycolate was obtained by the above procedure using 10 cc. of baseand 4.8 grams of glycolic acid, the sblvent being special denaturedalcohol No. 30. A white solid was obtained. a The aconitate was preparedin similar manner using 5 cc. of base and 5.45 gramsof aconitic acid,the solvent being special denatured alcohol No. 30. The aconitate saltwas obtained as a sirup and having an acid reaction. A neutral salt wasobtained by changing the amount of aconitic acid used to 7.25 grams.

1 The adipate was obtained in the form of a salt combining 1 mol. ofbase with 2 mols. of acid by carrying out the reaction as disclosedabove using 10 cc. :of base and 6.08 grams of adipic acid, the solventbeing special denatured alcohol No. 30. The 'adipate was a white solidM. P. 103-105". Analysis-N calculated 5.27; N found 5.27.

The fumaratewas obtained by the same procedure using 10 cc. of base and4.85 grams of furnaric acid, the solvent being special denatured alcoholNo. 30. A white crystal solid salt formed M. P. 220-223.

The'malonate was obtained in the. same manner using 10 cc. of base and 5grams ofmalonic acid, with ether as the solvent. The salt'o'btainedcombined 1' mol. of

base with 2'mols. of acid. White'solid, M. P. 124-125 gtnailySin-Ncalculated5.86; found 5.79. f

EXAMPLE 2 Preparation of N,N-bis-( 2-heptyl) -ethyleizediamirre andsalts thereof 131.1 g. of 2-heptylamine and 214 g. of ethylene bromidewere warmed on the steam-.bath yielding. a brownish-red sirup. Onstirring the'sirup with ether .it slowly dissolved and precipitated awhite solid. The solid was filtered 0E and recrystallized from methanol,P. 282. Calcd. for C H N -2HBn N, 6.7,; Br, 38.2. Found: N, 6.09; Br,36.0. The picrate had M. P. 150".

The hydrobromide was treated with sodium hydroxidesolutionyieldinganoily upper layer which was extracted withether. Theether layer .wasdried. over solid sodium hydroxide, the ether removed.and the residue frac-v tionated. The .product had B. P. 125-127" at '2mum,

10.9. Found: C, 73.41, 7305; H, 12.50, 12.36; N, 10.58.

2 EXAMPLE 3 Preparation of N,N-dicyclohexylethylrrediamine' and saltsthereof following salts were obtained by adding the orresponding acidstoan alcohol solution of thebase crystals, M. P. 246 (bar.).

r 7 until no'further precipitation occurred and recrystallizing thecrude products from water:

Dihydrochloride, white plates, M. P. 315 (ban).

for c,,H,,N,-2Hc1: N, 9.43. Found: 9.14. Dihydrobromide, white plates,M. P. 339 dec. (bar.). Dinitrate, small white crystals, dec. 230 (ban).Diflavianate, small yellow crystals, dec. 312 (ban). Phosphate, whiteplates, M. P. 313 (ban).

Picrate, yellow crystals, M. P. 218 (ban).

Sulfate, large white plates, M. P. above 350 (ban).

The acetate was prepared in ether from the base and acetic acid as largewhite crystals, M. P. 144".

The acetate in water solution on treatment with'potassium cyanateyielded the corresponding bis-urea, small white crystals from dilutealcohol, M. P. 248 (ban).

' The dinitroso compound was prepared from the acetate and sodiumnitrite in water. White crystalline flakes, M. P. 1301 (ban).

Calcd.

EXAMPLE 4 Preparation of N,N'-bis-(4-methyl-2-pentyl)- ethylenediamineEXAMPLE 5 Preparation of N,N'-bis-(3,5,5-trimethylhexyl)-ethylenediamine and its salts 286 g. of 3,5,5-trimethylhexylamine and 50g. ethylene chloride were warmed on the steam-bath for several daysafter which time the reaction mass was very viscous and jellied oncooling. Water was added followed by a strong solution of sodiumhydroxide. This was extracted with ether, the extract dried over solidsodium hydroxide, the ether removed and the residue fractionated. Thefractions boiling between 123 and 200 at 0.06 to 0.08 mm. were combinedand refractionated. Most of the material distilled 149to 154 at 1.2 mm.and had 11 1.4548.

' The acetate was prepared by adding acetic acid to an ethereal solutionof the base and recrystallizing from ethyl acetate, small white flakes,M. P. 105. Calcd. for CzoH NgZCHgCOOHZ N, Found: N,

' The vhydrobromide was prepared by adding hydro- .bromic acid to analcoholic solution of the base and recrystallizing the product fromdilute alcohol, fine white Calcd. for,C- H N -2HBr:

N, 5.36; Br. 30.6. Found: N, 5.8; Br, 33.15.

- '.The hydrochloride was prepared in the same manner as thehydrobromide. (ban).

The nitrate was obtained as above. Large white flakes, M.,P. 214 (ban).Solubility 2.14 mg.-/ml. at 30.

The phosphate obtained as above was recrystallized from dilute alcohol.

The sulfate was recrystallized from water. White crys tals, M. P. 290(ban). dec. Calcd. for C H N O S:

Large white plates, M. P. 256

N, 6.83. Found: N, 6.31.

EXAMPLE 6 v Preparation of N,N'-bis(2-thenyl)-ethylenediamine and a saltthereof In a 500 ml. three-necked flask, fitted with stirrer, condenserand thermometer, were mixed 42 g. (0.5 mol.) of

. in vacuo.

mol.). The mixture was stirred and heated to gradually raise thetemperature. At 60 a vigorous reaction began. Heating was stopped and anice-bath applied to the flask. The internal temperature rose to. 73 andthe reaction mixture solidified. 200 ml. of 50% aqueous alcohol wereadded and stirred and the mixture was heated an additional 1 /2 hours.After cooling, the reaction product was filtered and washed with water.The white product was amorphous and did not dry well, nor could it becrystallized.

It was dissolved in 250 ml. hot water, cooled, and made alkaline with40% sodium hydroxide. The free base which separated was not very solublein ether, and was taken up in benzene, dried over sodium hydroxide andobtained as a colorless, viscous oil on removing benzene The oil wasconverted to diacetate by dissolving in 200 ml. ethyl acetate and adding12 ml. glacial acetic acid. The precipitated salt was filtered, washedwith ethyl acetate and dried, M. P. 84 (bar.).

In essentially the same manner as taught by Example 6, one may alsoreact an alkylene diamine such as ethylenediamine and an acid, as, forexample, hydrochloric, sulfuric or formic acid, to form the di-acid saltof the alkylene diamine, and using 0.25 mol. of the di-acid salttogether with half a mol. of formaldehyde, half a mol. of the followingcompounds may be reacted therewith to form the corresponding symmetricaldisubstituted alkylene diamines: cyclohexanone, 2,3 and4'-methylcyclohexanone, 4 methoxy cyclohexanone, cyclopentanone, 2-methylthiophene, isoquinoline, 3-'nethyl-isoquinoline and quinaldine.

EXAMPLE 7 48.2 g. of beta-phenylethylamine and 18.8 g. ethylene bromidewere warmed on the steam-bath. The reaction was vigorous and afterstanding some time at room temperature the mass crystallized. Thereaction product was made alkaline, extracted with ether and the etherlayer extracted with dilute'acetic acid. The acid extract was madealkaline, extracted with ether; the ether layer dried over magnesiumsulfate, filtrated through carbon and the ether removed. The residue wasthen distilled; all volatile material was taken off up to 210 at 1.5 mm.The residue was taken up in ether and treated with glacial acetic acid.The solid was filtered off and recrystallized from ethyl acetate to givesmall white needles, M. P. 114'.

In the same manner as taught hereinabove, an alkylene dihalide such as1,2-dichloroethane may be reacted with laurylarnine,3-methyl-cyclohexylamine, m-nitraniline, 2- amino-6-methyl-pyridine,2-amino-4-methyl pyridine, 2- amino-S-methyl-pyridine,Z-amino-3-methyl-pyridine, 2- amino-thiazole, or Z-amino-S-methyl-furanto form the symmetrically di-substituted alkylene diamine and desiredsalts thereof. The reaction mixture, after making strongly basic withalkali such as sodium hydroxide, may be extracted with ether and theether extract distilled to obtain the desired product as a crystallineor solid residue. 4

EXAMPLE 8 Preparation of N-ethyl-ethylenediamine and a salt thereof vtheaqueous filtrate made alkaline with solid NaOH,

till two layers appeared. .The organic layer was separated and furtherdried over NaOI-L The product was distilled through a small column. B.Pt.: 126-130 C.

9 N-ethyl-ethylenediamine di-picrate: M. Pt. 21011 C. Analytical(di-picrate): Calculated, N=20.60. Found: N==20.5l.

EXAMPLE 9 Preparation ofN,N'-di-3,3'-octylmercapt0propylethyleneriz'ainine zene solution waswashed with water, dried over anhydrous magnesium sulfate, the benzenedistilled ofl? and the residue fractionated. The first fraction wasunchanged diallylethylenediamine and octyl mercaptan, the second boiledat 180-198/4.64.8 mm.

EXAMPLE Preparation of N,N-di-beta-ethoxyethylethylenediamine To arefluxing solution of 50 cc. of redistilled 80% ethylenediamine in 50cc. absolute alcohol 60 g. of betaethoxyethyl chloride was added over aperiod of one hour and refluxing was continued for 26 hours. On coolinga solid crystallized out. An equal volume of water was added and most ofthe alcohol distilled off. The resulting solution was made stronglyalkaline, extracted with benzene, the benzene solution dried overanhydrous magnesium sulfate, filtered, the benzene distilled oil? andthe residue distilled under atmospheric pressure. Most of the materialdistilled between 230 and 290. The slightly yellowish distillate wasfractionated through'a glass helices packed column under reducedpressure. The main fraction distilled at l08116/ 3.8-3.9 mm.

Following the procedures disclosed hereinabove, the following compoundsmay be made and fall within .the general scope of the invention. Thesecompounds" are also deemed useful, either as the free base or theacidaddition salts, for their therapeutic action, as intermediates orfor the purpose of isolating penicillin salts.

Monosubstituted diamines: Starting materials N -undecylethylenediamineUndecylaldehyde and ethylenediamine diformate.

N-heptylethylenediamine Heptaldehyde and ethylenediamine diformate.N-(3,5,5-trimethylhexyl)ethyl- 3,5,5-trimethylhexaldehyde andenediamine. N -2-thenylethylenediamine N-pchloro or bromophenyl ethylenediamine. N-v mnllyl cthylcncdiamine.

N -2,4 01' other dichloro or bromophenylethylene diamine. Ne? or4-pyridylethyl-ethylenediamine. N-2-or 4quinolylethyl ethylenedlamine. N-4-methoxycyelohexyl-ethylenediamine. Disubstituted diamines: N ,N'-di-n-heptyleth ylenediamine.

N ,N -di-u.ndecyl eth ylcnediamine.

N ,N -dicycl opentylethyleno 'diamine.

N,N di-4-methoxy cyclohexylethylene diamine.

N ,N divanillylethylcnedia mine. I

N -c1yclohexy1-N -ethyleth ylenemine. N-benzyl-N -vanillylethylenediarnine. I N -methy1 N phenylethylene "diamine.

N ,N-di-undecyleneyleth ylene- I diamiue. V

N ,N' -di omega brompropyl ethylenediamine'.N,N-di-omega-hydroxypropyltrimethylenediamine. N ,N (1i betavinyloxyethyl eth ylenediamine.

N -,N di beta ca'rboxamido methyl-ethylenediamine.

ethylenediamine diformate. Thiophene, formaldehyde, ethylenediamine-dlH01 salt. N-phenylethylene diamine and C130! Bra. Vanillin,ethylsnediamiue ditormate. N-phenylethylene diamine and C1: or Brzor4-piciline, formaldehyde, ethyleuediamine di-HOl salt. 2- or-quinaldine, formaldehyde,

ethylenediaminedi-HOI salt.

'4-methoxycyclohexanone and eth- Trimethylcnechlorohydrin meth'ylenediamine. Vinylbctachlorethylether and ethylenedlamine.

amine Chlcracetamideand ethyienedi- 10 The following examples illustratethe preparation'of penicillin salts from the corresponding substitutedalkylenedia'mines.

EXAMPLE 11 Preparation of N-mono-benzylethylenediamine di-penicillin-G224 mg. of N-rnono-benzylethylenediamine dihydrochloride was dissolvedin about 2 cc. of water. To this a solution of 712 mg. of sodiumpenicillin dissolved in 2 'to' 3 cc. of water was'added. A clearsolution resulted from which an oil'precipitated in a few minutes. Thewater layer was poured oif and the oil placed in a desiccae tor overphosphorus pentoxide. In a short time white crystals appeared and all ofthe oil solidified. On heating at any temperature between 124 and 191,this material melted and immediately solidified to a white foamy, veryviscous mass. At 191 bar.) the solid melted to a liquid which darkenedand decomposed without giving the .white foamy mass. f

EXAMPLE 12 Preparation of N -m0n0 (p hydroxybenzyl) -ethylenedi- 3 aminedi-penicillin-G 240 mg. of N-mono (p hydroxybenzyl)-ethylenediaminedihydrochloride was dissolved in about 2 cc. of water. a To thissolution 712mg. of sodium penicillin dis-. solved in about 2 to 3 cc. ofwater was added. An ime mediate white granular precipitate formed whichwas filtered off, washed with water and dried over phosphorus pentoxide.The M. P. was 131 (ban).

EXAMPLE 13 The air-dried powder has a broad melting point, sintering. atmelting above to a cloudy liquid becoming clear at135. it has 7.7-9.6%water (of crystallization), which can be removed on drying in 21 Fischerpistol. Analysis of the dried sample showed: C, 63.86; H, 6.41; S, 6.74.Calcd. for

2C16H18O4N2S is zo z C, 63.8 H, 6.20; S, 7.08. Ash was negligible. Assayshowed on a dry basis 1235 units per'mg. (calcd. 1307).

EXAMPLE 14 Preparation of N,N'-dipiperonyl 'thylenediamine di-penicillinG To a solution of 1.07 g. sodium penicillin in about 2 ml. cold water,a solution of 0.7 g. N,N-dipiperonylethylenediamine acetate in about .2ml. cold water. was.

slowly added with stirring. The white insoluble solid was filtered 01f,washed with water and dried over phosphorus pentoxide.

EXAMPLE 15 Preparation of N,N-difurfurylethylenediamine di-penicillin-GSodium penicillin (1.07 'g.) is dissolved in about 2 ml. water cooled inan ice-bath. To the clear solution, 0.5 g. ofN,N'-difurfurylethylenediamine acetate dissolved in about 2 ml. of coldwater is slowly added with stirring.

A white, insoluble, crystalline powder is formed'which,

is filtered oif, washed with cold water and dried in a desiccator overphosphorus pentoxide. 1

It is obvious that the insoluble organic base penicillin salts formedcontain two mols. of penicillin for each mol. of organic base when adi-salt of the substituted diamine is used and when an excess ofpenicillin salt is present, as is indicated by the analysis of theN,N'-dibenzylethylenediamine salt, andby the assays of the N,N-di--benzyl-, N,N'-difurfuryl and N,N'-dipiperonylethylenediamine penicillinsalts. The best procedure for insuring the formation of a di-salt is toadd the base salt water solution into the acid or penicillin solution,and if relatively large crystals are desired, the rate of additionshould, be slow with a relatively low concentration during reaction.Another way to insure the formation of a di-salt is to add the twoaqueous solutions simultaneously in such a way as to get equivalentamounts reacting at any one time.

It is also possible to obtain the mono-salt, that is the combination ofone mol, organic base to one mol, of penicillin. If one were to reversethe addition described above, namely by adding the solution ofpenicillin salt to the water solution of the base salt, one could obtainthe mono-penicillin salt.

Penicillin salts can also be prepared by adding nonaqueous solutions offree penicillin to non-aqueous solutions of the organic bases by usingsuitable solvents such as ether, acetone, ethylacetate, amylacetate,etc. This procedure can be carried out provided one avoids an excess ofbase which inactivates or decomposes the penicillin.

Besides the penicillin salts hereinabove described and those made fromthe alkylenediarnines mentioned, the following monoand di-penicillinsalts are also deemed useful for the reasons indicated.

N-octylethylenediamine di-penicillin N,N-di-propargylethylenediaminedi-penicillin N,N-dicrotylethylenediamine dipenicillinN,N-di-phenylethylenediamine di-penicillin N,N-di-l( or 2) naphthylethylene diamine di-penicillin N,N'-di-2-pyridylethylenediaminedi-penicillin N-benzhydrylethylenediamine di-penicillinN,N'-di-benzhydrylethylenediamine di-penicillinN-veraterylethylenediamine di-penicillin N,N-di-veraterylethylenediaminedi-penicillin N-benzyl N p-methoxybenzylethylenediamine di-penicillinN,N'-dibenzyl-l-methylethylenediamine di-penicillinN,N-dicyclohexylethylenediamine mono-penicillin N,N-diamylethylenediamine mono-penicillin N-ethyl-N-phenylethylenediaminemono-penicillin Penicillin salts, prepared in accordance with theillustrative examples, are listed with their melting points:

Organic base salt Form of di-penicil- M. P., 0.

lin-G salt Nili-dibenzylethylenediarnine diace- WVhitg crystalline021110-135.

a e. pw N,N-(lipiperonylcthylenediamine White pw (1. or 112-119.

diacetatc. colorless crysta s. N,N'-bis-(p-clilorobenzyD-ethyl- Whitecrystals 110-119. enediaiuine diacetatc. N,N'-bis-(2,4-dichlorobenzyl)-ethyl- Yellowish prisms. 95-100.

enediamine diacetate. N,N bis (p -nitrobenzyl) cthylenc- White crystals-95-100.

diamine diacetate. N,N bis (p hydroxyoenzyl) do 140-145.

cthylc nediamino dihydrochloride. N,N bis (p methoxyberizyl) (lo100-103.

ethylenediamine diacetate. N .N bis (p aminobenzyl) cthyl- White,granular 144-8.

eiietliamine (lihydroohloride. cryst. N -bcnzyl -N (alpha -cthylbenzyl)White crystals. 105-8.

ethylenediamine dihydrochlcride. i: ,N -bis- (heta-plienylethyl) -ethyl-.-..do 95-102. cnediamine diacetntc.

1N,N bis (gamma phenylpropyl) .d 78-83.

athylenediamine dihydrochloride. 1,3 bis (benzylamino) propane .d0100-102.

diacetate. 1,5 bis (henzylamino) pentane White glass.. 120-140.

diacetate.

N,N-di-methallylethylenediamine di-penicillin Organic base salt Form ofdi-penicil- 1W1 P., C.

liu-G salt N,N difurfurylethylenediamine (11- White crystalline 83-86.

acetate. pwd.

N,N d1 2 thenylethylenediamine White crystals... 145-7.

diacetate.

N,N dicyclohexylethylenediamine do 155-6.

diacetatc.

N,N bis (4 methyl 2 pentyl) Colorless solid 165.

ethylenedlamine dlacetate.

N,N bis (2 lieptyl) ethylenedia- Crystalline solid 85 mine diacetate.

N ,N bis (3,5,5 trimethylhexyl) White crystals -95.

ethylenediemlne diacetate.

N,N bis (p methylbenzyl) ethyldo 90-97 enediamine diacetate.

1,10 -tbits (benzylamino) deeane di- White solid 100.

ace a e.

N,N his (ethyl) ethylene diamine White, cryst 172-3 dihydrochloride.

N,N bis (n propyl) ethylenedia- White, granular. 120.

mine diacetate.

N ,N bis (lsopropyl) ethylenedia Fine white cryst -160.

mine dlacetate N,N bis (n butyl) ethylenedia .do.

mine diacetate.

N ,N is (isobutyl) ethylenedia Whlte solid mine diacetate.

N ,N bis (sec. butyl) ethylenedia White, granular." 135-145.

mine diacetate.

N ,N bis (1 cyclopropylethyl) White cryst 73.

ethylenediamine dihydrochloride.

N,N bis (hexahydrobenzyl) -ethyl .do... 151.

enediamine dihydrochloride.

N,N bis (4 methylcyclohexyl 1) (lo 15b.

ethylenediamine dihydrochloride.

N ,N dimethylethylenediamine di White solid 147119.

hydrochloride.

N,N-dibenzhydrylethylenediamined0 118-119.

dlhydrochlorlde.

N -metliyl-ethylenediainine dihydro- .do 252-3.

chloride.

N dodeeyl ethylenediamine di .do 232-3.

hydrochloride.

N,N' di beta ethoxyethyl-ethyl .d0 85-90.

enediamine diacetate.

N,N di allylethylenedlamine (ll White cryst above 85 hydrochloride.(foam).

N ,N diisopropyl decamethylene White solid 175.

diamine-diiodide.

N ,N di-n octyldecamethylene -dia- .....(10 170.

mine-diacetate.

N,N di beta cyclohexylethyl d0 118-120.

ethylenediamine-dihydrochloride.

N (2 metlioxy 6 chloro 9 acridyl) Yellow solid above ethylenediaminediacetate. (foam).

N mono beta cyclchexylethyl White solid.. 231-3.

ethylenediamine-dihydrochloride.

1,2 ethylenediamine bis (N 2 do 108.

heptyl acetamide) (liacetate.

With regard to crystal size, the rapid addition of a water solution ofthe base salt to a water solution of the penicillin salt will usuallyproduce very finely divided crystals of micro size. These are highlyWater retentive and difficult to wash. Where relatively large crystalsare desired, it is important to bring the two aqueous solutions ofreactants together in low concentration. This can be done by adding thereactants together in small amounts to a relatively large body of Water,thus obtaining the low concentration necessary.

The penicillin salts obtained as described are insoluble in most of theusual laboratory solvents, but have very appreciable solubility informamide and dimethyl .formamide. Many are only sparingly soluble orsubstantially insoluble in water.

The solubility properties of the penicillin salts of the invention aresuch that many substituted alkylene diamines could be used in any stageof the recovery process for the isolation of penicillin. Since asubstantial number of compounds, particularly those of higher molecularweight, are either insoluble or only sparingly soluble in water, aprecipitation from the buffered penicillin extract is possible. Withregard to N,N-dibenzylethylene- .diamine, for example, the free basecould be used for precipitation of penicillin from the amylacetateextracting liquors since the base is soluble in this medium. Thediacetate or any other water-soluble salt could, of course, be used forthe aqueous precipitation. The versatility of these compounds is clearlyobvious.

When the diamine penicillin salts are used for therapeutic purposes,they may be used for injection either with 13 a spreading agent such ashyaluronidase, with a suspending agent such as carboxymethyl celluloseor pectin, or in a vegetable oil vehicle either with beeswax or aluminummonostearate gel, the composition being made up in substantially thesame manner as any other sparingly soluble penicillin salt known to theart.

The diamine penicillin salts herein disclosed vary in their solubilityin water from sparing solubility to substantial insolubility. Because ofthis action, there is a variation in their therapeutic efiects rangingfrom quickly measurable blood levels to delayed blood levelmeasurements. The clinician is therefore given a wide choice ofpenicillin products with varying times of onset of action. Furthervariations may be made by mixing fast-acting and slow-acting compounds,whether this involves combinations of the diamine penicillin orcombinations of procaine penicillin or other known compounds with one ormore compounds of the invention.

Many modifications and changes within the skill of the art arecontemplated without departing from the scope of the invention asdefined the appended claims.

This application is a division of application Serial No. 306,514, filedAugust 26, 1952, now Patent No. 2,739,981, which in turn is acontinuation-in-part of application Serial No. 174,115, filed July 15,1950, now Patent No. 2,627,491.

We claim:

1. As new compounds, the water-soluble lower aliphatic acid-additionsalts of N,N'-bis-(3,5,5-trimethylhexyl)- ethylenediamine.

2. The new compound, N,N'-bis-(3,5,5-trimethylhexyl)- ethvlenediaminediacetate.

References Cited in the file of this patent Zienty et al.: I. A. C. 8.,vol. 67, pp. 1040 (1945), Linsker et al.: J. A. C. 8., vol. 68, 1432(1946).

1. AS NEW COMPOUNDS, THE WATER-SOLUBLE LOWER ALIPHATIC ACID-ADDITIONSALTS OF N,N''-BIS-(3,5,5-TRIMETHYLHEXYL)ETHYLENEDIAMINE.